EP2324028A2 - Agents thérapeutiques 414 - Google Patents

Agents thérapeutiques 414

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Publication number
EP2324028A2
EP2324028A2 EP09785441A EP09785441A EP2324028A2 EP 2324028 A2 EP2324028 A2 EP 2324028A2 EP 09785441 A EP09785441 A EP 09785441A EP 09785441 A EP09785441 A EP 09785441A EP 2324028 A2 EP2324028 A2 EP 2324028A2
Authority
EP
European Patent Office
Prior art keywords
pyrimidin
pyrazolo
propanamide
oxy
pyridyl
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Withdrawn
Application number
EP09785441A
Other languages
German (de)
English (en)
Inventor
Stuart Norman Lile Bennett
Peter Gustaf Bonn
Mikael Dan Brink
Roger John Butlin
Leonie Campbell
Robert Darren Morse Davies
Jonas Rickard FÄGERHAG
Ulrik Jurva
Helen Claire Pointon
Graeme Richard Robb
Volker Schnecke
Anette Marie Svensson Henriksson
Rolf Peter Walker
Michael James Waring
Christer Ralf Westerlund
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
AstraZeneca AB
Original Assignee
AstraZeneca AB
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Filing date
Publication date
Application filed by AstraZeneca AB filed Critical AstraZeneca AB
Publication of EP2324028A2 publication Critical patent/EP2324028A2/fr
Withdrawn legal-status Critical Current

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Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/04—Ortho-condensed systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/04—Anorexiants; Antiobesity agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/06—Antihyperlipidemics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
    • A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00

Definitions

  • the present invention relates to a group of 2- ⁇ [l-substituted-lH-pyrazolo[3,4- ⁇ i]pyrimidin-4-yl](thio,oxy or amino)-iV-(heteroaryl)alkanamides which are useful in the treatment or prevention of a disease or medical condition mediated through glucokinase (GLK or GK).
  • GK Activators GKAs
  • GKAs GK Activators
  • GKAs activate hepatic GK thereby stimulating hepatic glucose uptake and suppressing hepatic glucose output.
  • the net pharmacological effect of GKAs is to lower blood glucose levels Therefore, such compounds may have utility in the treatment of Type 2 diabetes and obesity.
  • the invention also relates to pharmaceutical compositions comprising said compounds and to methods of treatment of diseases mediated by GLK using said compounds.
  • G-6-P glucose-6-phosphate
  • GLK glucokinase
  • GLK has a high (6-1OmM) Km for glucose and is not inhibited by physiological concentrations of G-6-P.
  • GLK expression is limited to a few tissues and cell types, most notably pancreatic ⁇ -cells and liver cells (hepatocytes). In these cells GLK activity is rate limiting for glucose utilisation and therefore regulates the extent of glucose induced insulin secretion and hepatic glycogen synthesis.
  • Maturity-Onset Diabetes of the Young Type 2 (MODY-2)
  • the diabetes is caused by GLK loss of function mutations.
  • Hyperglycaemia in MODY-2 patients results from defective glucose utilisation in both the pancreas and liver.
  • Defective glucose utilisation in the pancreas of MODY-2 patients results in a raised threshold for glucose stimulated insulin secretion.
  • rare activating mutations of GLK reduce this threshold resulting in familial hyperinsulinism.
  • hepatic glucokinase activity is also decreased in type 2 diabetics.
  • GLK global or liver selective overexpression of GLK prevents or reverses the development of the diabetic phenotype in both dietary and genetic models of the disease.
  • acute treatment of type 2 diabetics with fructose improves glucose tolerance through stimulation of hepatic glucose utilisation. This effect is believed to be mediated through a fructose induced increase in cytosolic GLK activity in the hepatocyte by the mechanism described below.
  • GLK and the K ATP channel are expressed in neurones of the hypothalamus, a region of the brain that is important in the regulation of energy balance and the control of food intake. These neurones have been shown to express orectic and anorectic neuropeptides and have been assumed to be the glucose-sensing neurones within the hypothalamus that are either inhibited or excited by changes in ambient glucose concentrations. The ability of these neurones to sense changes in glucose levels is defective in a variety of genetic and experimentally induced models of obesity. Intracerebroventricular (icv) infusion of glucose analogues, that are competitive inhibitors of glucokinase, stimulate food intake in lean rats. In contrast, icv infusion of glucose suppresses feeding.
  • icv Intracerebroventricular
  • GLK activators of GLK may decrease food intake and weight gain through central effects on GLK. Therefore, GLK activators may be of therapeutic use in treating eating disorders, including obesity, in addition to diabetes.
  • the hypothalamic effects will be additive or synergistic to the effects of the same compounds acting in the liver and/or pancreas in normalising glucose homeostasis, for the treatment of Type 2 diabetes.
  • the GLK system can be described as a potential "Diabesity" target (of benefit in both Diabetes and Obesity).
  • GLK is also expressed in specific entero -endocrine cells where it is believed to control the glucose sensitive secretion of the incretin peptides GIP (glucose-dependent insulinotropic polypeptide) and GLP-I (Glucagon-Like Peptide- 1) from gut K-cells and L- cells respectively. Therefore, small molecule activators of GLK may have additional beneficial effects on insulin secretion, b-cell function and survival and body weight as a consequence of stimulating GIP and GLP-I secretion from these entero-endocrine cells.
  • a group of novel activators of GLK has been found containing a lH-pyrazolo[3,4- d]pyrimidin-4-yl core.
  • N-(Thiazolyl)-2-[(l-phenyl-lH-pyrazolo[3,4-d]pyrimidin-4- yl)thio]acetamide is disclosed in Phosphorus, Sulfur and Silicon, vol 178, 2003, ppl795- 1805 which is concerned with antimicrobial activity of related compounds. Similar compounds are also known from commercially available Chemical Libraries.
  • WO98/35944 discloses that compounds of formula R 1 R 2 N-C(O)-C(R 3 )(R 4 )-X-R 5 in which R ⁇ R 5 are each individually selected from a wide range of substituents and X is oxygen or sulfur are useful in treating bulimia and obesity by virtue of their activity at the NPY receptor antagonists.
  • R 5 may be IH- pyrazolo[3,4-d]pyrimidin-4-yl or 4- aminopyrazolo[3,4-d]pyrimidin-6-yl.
  • a and B are each either N or CR 6 , provided that at least one of A and B is CR 6 ;
  • X is C or N;
  • Y is CH or N;
  • R 1 is (l-6C)alkyl, aryl, aryl(l-6C)alkyl or HET-I wherein the aryl, aryl(l-6C)alkyl and HET-I are optionally substituted by one, two or three groups independently selected from halo, (l-4C)alkyl, (l-4C)alkoxy, trifiuoromethyl, (l-6C)alkylthio, (l-6C)alkylsulf ⁇ nyl, (1- 6C)alkylsulfonyl, cyano, carboxy, (l-6C)alkoxycarbonyl, carbamoyl, N-(I- 4C)alkylcarbamoyl, JV,iV-di(l-4C)alkyl
  • R 11 is independently selected from halo, (l-4C)alkyl, (l-4C)alkoxy, trifluoromethyl, (1- 6C)alkylthio, (l-6C)alkylsulfmyl, (l-6C)alkylsulfonyl, cyano, carboxy, (1- 6C)alkoxycarbonyl, carbamoyl, JV-(I -4C)alkylcarbamoyl, JV,iV-di(l-4C)alkylcarbamoyl, aminosulfonyl, (l-6C)alkylaminosulfonyl, di(l-6C)alkylaminosulfonyl, (1- 4C)alkanoylamino, hydroxy(l-4C)alkyl, (l-4C)alkoxy(l-4C)alkyl, (l-4C)alkylS(0)p(l- 4C)alkyl (wherein p is 0, 1 or 2),
  • HET-3 and HET-3A are each independently either a 5- or 6-membered, C-or N- linked unsubstituted heteroaryl ring containing 1 , 2 or 3 ring heteroatoms independently selected from O, N and S, or a A-, 5- or 6-membered, C- or N- linked unsubstituted saturated heterocyclyl ring containing one ring heteroatom selected from O, N and S; L is S, O or NR 12 ; and R 12 is H or (l-4C)alkyl; but excluding
  • a and B are each either N or CR 6 , provided that at least one of A and B is CR 6 ;
  • Z is C or N; wherein X, Y and Z are chosen such that at least two of X, Y and Z are N, the ring containing them is aromatic and any ring nitrogen atom is not quaternised;
  • R 1 is (l-6C)alkyl, aryl, aryl(l-6C)alkyl or HET-I wherein the aryl, aryl(l-6C)alkyl and HET-I are optionally substituted by one, two or three groups independently selected from halo, (l-4C)alkyl, (l-4C)alkoxy, trifiuoromethyl, (l-6C)alkylthio, (l-6C)alkylsulfmyl, (1-
  • HET-I is a 5- or 6-membered, C-linked heteroaryl ring, or a fused bicyclic ring system of formula -D-E, wherein ring D is attached to Z and is 6-membered aryl or heteroaryl ring and ring E is a 5- or 6-membered heteroaryl, heterocyclyl or cycloalkyl ring which is fused to ring D at any available position;
  • R 2 is (l-6C)alkyl optionally substituted by one or two hydroxy or by one of the following: carboxy, carbamoyl, JV,iV-di(l-4C)alkylcarbamoyl, (l-6C)alkoxycarbonyl, a group -
  • R 2 is a group -(CHR 4 ) n -P-Q wherein n is 1, 2, 3 or 4;
  • P is a linker selected from O, SO 2 , SO 2 NH, NHSO 2 , CONH and NHCO;
  • Q is selected from (l-6C)alkyl, (3-6C)cycloalkyl and a 4-, 5- or 6-membered heterocyclyl (wherein said heterocyclyl ring contains 1 , 2 or 3 heteroatoms independently selected from
  • R 3 is a group HET-2 wherein HET-2 is a 5- or 6-membered C-linked monocyclic heteroaryl ring, containing a nitrogen atom in the 2-position and optionally 1 or 2 further ring heteroatoms independently selected from O, N and S; or HET-2 is an 8-, 9- or 10- membered C-linked bicyclic heteroaryl ring containing a nitrogen atom in the 2-position with up to five further ring heteroatoms independently selected from O, N and S; wherein HET-2 is optionally substituted on an available carbon atom, or on a ring nitrogen atom provided it is not thereby quaternised, with 1 or 2 substituents independently selected from R 11 ; each R 4 is independently selected from hydrogen, hydroxy, methyl and ethyl; provided that when n is >1, then no more than two R 4 groups are hydroxy;
  • R 5 is H, (l-4C)alkoxy or (l-4C)alkyl
  • R 6 is H, (l-4C)alkoxy or (l-4C)alkyl
  • R 7 is H or (l-4C)alkyl
  • R 8 is (l-4C)alkyl
  • R 9 is H or (l-4C)alkyl
  • R 10 is H or (l-4C)alkyl; R 11 is independently selected from halo, (l-4C)alkyl, (l-4C)alkoxy, trifluoromethyl, (1-
  • HET-3 and HET-3A are each independently either a 5- or 6-membered, C-or N- linked unsubstituted heteroaryl ring containing 1 , 2 or 3 ring heteroatoms independently selected from O, N and S, or a 4-, 5- or 6-membered, C- or N- linked unsubstituted saturated heterocyclyl ring containing one ring heteroatom selected from O, N and S; L is S, O or NR 12 ; and
  • R 12 is H or (l-4C)alkyl; but excluding
  • aryl refers to phenyl, naphthyl or a partially saturated bicyclic carbocyclic ring containing between 8 and 12 carbon atoms, preferably between 8 and
  • Example of partially saturated bicyclic carbocyclic ring include: 1,2,3,4-tetrahydronaphthyl, indanyl, indenyl, 1, 2, 4a,5, 8, 8a-hexahydronaphthyyl or l,3a-dihydropentalene.
  • Examples of "aryl(l-6C)alkyl” include any of the above examples of “aryl” in conjunction with any of the examples of “(l-6C)alkyl” hereinafter.
  • HET-I groups when HET-I is a 5- or 6-membered C-linked heteroaryl ring include thiazolyl, isothiazolyl, thiadiazolyl, pyridyl, pyrazinyl, pyridazinyl, pyrazolyl, imidazolyl, pyrimidinyl, oxazolyl, isoxazolyl, oxadiazolyl and triazolyl. More suitably
  • HET-I groups are pyridyl or pyrazinyl, particularly 2-pyridyl, 4-pyridyl and pyrazinyl.
  • Suitable HET-I groups when HET-I is of formula -D-E include indanyl, benzodioxolyl, benzimidazolyl, benzthiazolyl, benzisothiazolyl, benzoxazolyl, benzisoxazolyl, quinolyl, isoquinolyl, benzofurazanyl, indolyl, indazolyl, cinnolinyl, quinazolinyl, quinoxalinyl, phthalazinyl, 1,5-naphthyridinyl, 1,6-naphthyridinyl, 1,7- naphthyridinyl, 1,8-naphthyridinyl, pyrrolopyridinyl, pyrrolopyrazinyl, pyrazolopyridinyl and imidazopyridinyl.
  • HET -2 examples include pyrrolyl, thiazolyl, isothiazolyl, pyrazolyl, imidazolyl, thiadiazolyl (1,2,4- and 1,3,4-), oxazolyl, isoxazolyl, triazolyl, 1,3,4- oxadiazolyl, 1,2,4-oxadiazolyl, furazanyl, tetrazolyl, pyridyl, pyrazinyl, pyridazinyl, pyrimidinyl, 1,3,5-triazinyl, imidazothiazolyl, benzimidazolyl, benzthiazolyl, benzisothiazolyl, benzoxazolyl, benzisoxazolyl, quinolyl, isoquinolyl, benzofurazanyl, indolyl, indazolyl, cinnolinyl, quinazolinyl, quinoxalinyl,
  • HET-3 and HET-3A as heteroaryl rings are furyl, pyrrolyl, thienyl, thiazolyl, isothiazolyl, thiadiazolyl, pyridyl, pyrazinyl, pyridazinyl, pyrazolyl, imidazolyl, pyrimidinyl, oxazolyl, isoxazolyl and triazolyl.
  • Suitable examples of HET-3 and HET-3A as saturated heterocyclyl rings are oxetane, azetidine, thietane, pyrrolidine, tetrahydrofuran, tetrahydropyran and piperidine. It will be appreciated that, where definitions of heterocyclyl groups HET-I, HET -2,
  • HET-3 and HET-3 A encompass heteroaryl rings which may be substituted on nitrogen, such substitution may not result in charged quaternary nitrogen atoms. It will be appreciated that the definitions of HET-I, HET-2, HET-3 and HET-3 A are not intended to include any O-O, O-S or S-S bonds. It will be appreciated that the definitions of HET-I , HET-2, HET-3 and HET-3A are not intended to include unstable structures.
  • Examples of the group Q as a 4-, 5-, or 6-membered ring heterocycle as hereinbefore defined include azetidinyl, oxetanyl, pyrrolidinyl, pyrrolidonyl, tetrahydrofuryl, tetrahydropyranyl, piperidinyl, morpholinyl, piperazinyl and thiomorpholinyl.
  • Particular examples of Q as a heterocycle include azetidinyl and pyrrolidinyl.
  • references herein to a compound of formula (I) will be understood to include reference to a compound of formula (IA), (IB) or (IC).
  • Compounds of Formula (I) may form salts which are within the ambit of the invention.
  • Pharmaceutically-acceptable salts are preferred although other salts may be useful in, for example, isolating or purifying compounds.
  • the invention relates to compounds of formula (I) as hereinabove defined or to a pharmaceutically-acceptable salt.
  • the invention relates to compounds of formula (I) as hereinabove defined or to a pro-drug thereof.
  • Suitable examples of pro-drugs of compounds of formula (I) are in- vivo hydro lysable esters of compounds of formula (I). Therefore in another aspect, the invention relates to compounds of formula (I) as hereinabove defined or to an in- vivo hydro lysable ester thereof.
  • alkyl includes both straight-chain and branched-chain alkyl groups.
  • references to individual alkyl groups such as “propyl” are specific for the straight chain version only and references to individual branched-chain alkyl groups such as t-butyl are specific for the branched chain version only.
  • (l-4C)alkyl includes methyl, ethyl, propyl, isopropyl and t-butyl.
  • Examples of (l-4C)alkyl include methyl, ethyl, propyl, isopropyl, butyl and tert- butyl; examples of (l-6C)alkyl include (l-4C)alkyl, pentyl and hexyl; examples of (1- 8C)alkyl include (l-6C)alkyl and heptyl; examples of (l-4C)alkoxy, (l-6C)alkoxy and (1- 8C)alkoxy include methoxy, ethoxy, propoxy, isopropoxy and tertbutoxy; examples of (1- 6C)alkoxycarbonyl include methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, isopropoxycarbonyl and tertbutoxycarbonyl; examples of (l-6C)alkoxycarbonyl(l- 4C)alkyl include methoxycarbonylmethyl, ethoxycarbonylmethyl, propoxycarbonylethyl, iso
  • the invention includes in its definition any such optically active or racemic form which possesses the property of activating GLK.
  • the synthesis of optically active forms may be carried out by standard techniques of organic chemistry well known in the art, for example by synthesis from optically active starting materials or by resolution of a racemic form.
  • certain compounds may exist in tautomeric forms and that the invention also relates to any and all tautomeric forms of the compounds of the invention which activate GLK.
  • compounds described in their pyrimidinol form may also be described as the pyrimidinone tautomer and vice versa. This implies nothing about the actual relative proportions of the two in physical samples.
  • the carbon atom to which R 2 is attached is a chiral centre.
  • this chiral centre has the S-configuration.
  • this chiral centre has the R-conf ⁇ guration.
  • certain compounds of the formula (1) and salts thereof can exist in solvated as well as unsolvated forms such as, for example, hydrated forms. It is to be understood that the invention encompasses all such solvated forms which activate GLK.
  • compounds of formula (I) in an alternative embodiment are provided pharmaceutically-acceptable salts of compounds of formula (I), in a further alternative embodiment are provided in-vivo hydrolysable esters of compounds of formula (I), and in a further alternative embodiment are provided pharmaceutically-acceptable salts of in-vivo hydrolysable esters of compounds of formula
  • each variable group are as follows. Such values may be used where appropriate with any of the values, definitions, claims, aspects or embodiments defined hereinbefore or hereinafter. In particular, each may be used as an individual limitation on the broadest definition of formula (I) (including formulas (IA), (IB) and (IC)). Further, each of the following values may be used in combination with one or more of the other following values to limit the broadest definition, or any sub-definition, of formula (I).
  • A is N and B is CR 6
  • A is CR 6 and B is N
  • R 1 is optionally substituted alkyl
  • R 1 is optionally suibstituted aryl
  • R 1 is optionally substituted aryl(l-6C)alkyl
  • R 1 is optionally substituted HET-I 10) R 1 is optionally substituted phenyl or pyridyl (particularly pyrid-2-yl or pyrid-4-yl, more particularly pyrid-2-yl)
  • R 1 is phenyl or pyridyl (particularly pyrid-2-yl), substituted in a 2-position relative to the point of attachment to Z
  • R 1 is phenyl or pyridyl (particularly pyrid-2-yl), substituted in a 2-position relative to the point of attachment to Z
  • R 1 is phenyl or pyridyl (particularly pyrid-2-yl) and R 1 is di-substituted, wherein one substituent is in a 2-position relative to the point of attachment to Z 14) optional subsitituents on R 1 are selected from halo (particularly chloro), (l-4C)alkyl, (l-4C)alkoxy, trifluoromethyl, (l-6C)alkylsulfonyl and cyano
  • R 1 is a fused bicyclic ring system of formula -D-E
  • R 2 is (l-6C)alkyl optionally substituted by one or two hydroxy or R 2 is a group - (CHR 4 ) n -P-Q
  • R 2 is a group -(CHR 4 ) n -P-Q
  • R 2 is a group -(CHR 4 ) n -P-Q; n is 1, 2, 3, or 4 (particularly 1 or 2); one R 4 is optionally hydroxy and the other R 4 groups (where applicable) are hydrogen or methyl; P is an oxygen linker and Q is (l-6C)alkyl, (3-6C)cycloalkyl or a 4-, 5- or 6-membered heterocyclyl, and Q is optionally substituted on an available carbon atom by hydroxy or (1- 4C)alkoxy
  • R 2 is a group -(CHR 4 ) n -P-Q; n is 1, 2, 3, or 4 (particularly 1 or 2); one R 4 is optionally hydroxy and the other R 4 groups (where applicable) are hydrogen or methyl; P is an oxygen linker and Q is (l-6C)alkyl, optionally substituted by hydroxy or (l-4C)alkoxy 20)
  • R 2 is selected from hexyl, butyl, isobutyl, isopropyl, ethyl, methyl, isopropoxymethyl, ethoxymethyl, cyclobutyloxymethyl, methoxymethyl, hydroxyethyl, hydroxypropyl, methylsulfonylethyl, isopropylsulfonylethyl, ethylsulfonylethyl, methylsulfonylaminoethyl, methylsulfonylaminomethyl, cyclopropyloxymethyl, ox
  • R 2 is selected from hexyl, butyl, isobutyl, isopropyl, ethyl, methyl, isopropoxymethyl, ethoxymethyl, cyclobutyloxymethyl, methoxymethyl, hydroxyethyl, hydroxypropyl, methylsulfonylethyl, methylsulfonylaminoethyl, hydroxyethoxymethyl, methoxyethyl, 1- methoxyprop-2yloxymethyl, dimethylaminoethyl, methylcarbonylaminomethyl, carboxyethyl, carbamoylethyl, N-methylcarbamoylethyl, methoxyethoxyethyl, methylcarbonyloxyethyl,
  • R 2 is selected from isopropoxymethyl, ethoxymethyl, cyclobutyloxymethyl, methoxymethyl, hydroxyethyl, hydroxypropyl, cyclopropyloxymethyl, oxetanyloxymethyl, hydroxyethoxymethyl, l-hydroxyprop-2-yloxymethyl, methoxyethyl, 1-methoxyprop- 2yloxymethyl, methoxyethoxyethyl 23) R 2 is selected from isopropoxymethyl, ethoxymethyl, cyclobutyloxymethyl, methoxymethyl, hydroxyethyl, hydroxypropyl, hydroxyethoxymethyl, methoxyethyl, 1- methoxyprop-2yloxymethyl, methoxyethoxyethyl
  • R 3 is selected from optionally substituted pyridyl, thiazolyl, pyrimidinyl, pyrazinyl, pyridazinyl, pyrazolyl, isoxazolyl and thiadiazolyl
  • R is a 6-membered ring
  • R is optionally substituted pyridyl or pyrazinyl
  • R is optionally substituted pyridyl
  • R is pyridyl, substituted at the para position relative to the point of attachment to the CONH group
  • R 3 is 2-pyridyl, substituted at the para position relative to the point of attachment to the CONH group
  • R 11 is selected from halo, (l-4C)alkyl, (l-6C)alkylsulfonyl, N,N-dialkylcarbamoyl and cyano 3I)
  • R 11 is selected from halo (particularly chloro or fluoro, more particularly chloro) or (1- 4C)alkyl (particularly methyl)
  • each R 4 is hydrogen
  • n is >1 and only one R 4 is not hydrogen 34) n is 1, 2 or 3 35) n is 1 or 2
  • P is an oxygen linger 47
  • NR > 9r R > 10 forms an azetidine ring, optionally substituted with hydroxy, hydroxymethyl or methoxy
  • NR 9 R 10 forms an azetidine ring, optionally substituted with hydroxy or hydroxymethyl
  • R 1 is phenyl or pyridyl, substituted in the 2-position relative to the point of attachment to Z with a substituent selected from halo (particularly chloro), (l-4C)alkyl, (l-4C)alkoxy, trifluoromethyl, (l-6C)alkylsulfonyl and cyano;
  • R 2 is (l-6C)alkyl optionally substituted by one or two hydroxy or R 2 is a group -(CHR 4 ) n -
  • n is 1, 2, 3, or 4 (particularly 1 or 2); one R 4 is optionally hydroxy and the other R 4 groups (where applicable) are hydrogen or methyl;
  • P is an oxygen linker
  • Q is (l-6C)alkyl, (3-6C)cycloalkyl or a 4-, 5- or 6-membered heterocyclyl, and Q is optionally substituted on an available carbon atom by hydroxy or (l-4C)alkoxy;
  • R 3 is pyridyl, substituted at the para position relative to the point of attachment to the
  • R 11 is selected from halo (particularly fluoro or chloro, more particularly chloro), (1-
  • R 1 being substituted in a 2-position relative to the point of attachment to Z will be understood to refer to the following substitution pattern, illustrated for R 1 is phenyl and pyrid-2-yl:
  • Particular compounds of the invention include any one or more of: 2- ⁇ [l-(2-chlorophenyl)-lH-pyrazolo[3,4- ⁇ i]pyrimidin-4-yl]oxy ⁇ -3-methoxy- ⁇ /-(5- methylpyridin-2-yl)propanamide;
  • the present invention provides a compound selected from one or more
  • the compounds of the invention may be administered in the form of a pro-drug.
  • a pro-drug is a bioprecursor or pharmaceutically acceptable compound being degradable in the body to produce a compound of the invention (such as an ester or amide of a compound of the invention, particularly an in- vivo hydro lysable ester).
  • prodrugs are known in the art.
  • pro-drugs are as follows.
  • An in- vivo hydro lysable ester of a compound of the invention containing a carboxy or a hydroxy group is, for example, a pharmaceutically-acceptable ester which is hydrolysed in the human or animal body to produce the parent acid or alcohol.
  • Suitable pharmaceutically-acceptable esters for carboxy include Ci to C ⁇ alkoxymethyl esters for example methoxymethyl, Ci to C 6 alkanoyloxymethyl esters for example pivaloyloxymethyl, phthalidyl esters, C3 to CscycloalkoxycarbonyloxyCi to C ⁇ alkyl esters for example 1-cyclohexylcarbonyloxyethyl; l,3-dioxolen-2-onylmethyl esters, for example 5-methyl-l,3-dioxolen-2-onylmethyl; and Ci_ 6 alkoxycarbonyloxyethyl esters.
  • An in- vivo hydro lysable ester of a compound of the invention containing a hydroxy group includes inorganic esters such as phosphate esters (including phosphoramidic cyclic esters) and ⁇ -acyloxyalkyl ethers and related compounds which as a result of the in- vivo hydrolysis of the ester breakdown to give the parent hydroxy group/s.
  • inorganic esters such as phosphate esters (including phosphoramidic cyclic esters) and ⁇ -acyloxyalkyl ethers and related compounds which as a result of the in- vivo hydrolysis of the ester breakdown to give the parent hydroxy group/s.
  • ⁇ -acyloxyalkyl ethers include acetoxymethoxy and 2,2-dimethylpropionyloxy-methoxy.
  • a selection of in- vivo hydro lysable ester forming groups for hydroxy include alkanoyl, benzoyl, phenylacetyl and substituted benzoyl and phenylacetyl, alkoxycarbonyl (to give alkyl carbonate esters), dialkylcarbamoyl and N-(dialkylaminoethyl)-N-alkylcarbamoyl (to give carbamates), dialkylaminoacetyl and carboxy acetyl.
  • a suitable pharmaceutically-acceptable salt of a compound of the invention is, for example, an acid-addition salt of a compound of the invention which is sufficiently basic, for example, an acid-addition salt with, for example, an inorganic or organic acid, for example hydrochloric, hydrobromic, sulphuric, phosphoric, trifluoroacetic, citric or maleic acid.
  • a suitable acid-addition salt may be one with hydrochloric, sulphuric, methanesulfonic or citric acid. It will be understood that an acid addition salt may be formed with any sufficiently basic group which may for example be in HET-I or may for example be a substituent R 2 .
  • a suitable pharmaceutically-acceptable salt of a benzoxazinone derivative of the invention which is sufficiently acidic is an alkali metal salt, for example a sodium or potassium salt, an alkaline earth metal salt, for example a calcium or magnesium salt, an ammonium salt or a salt with an organic base which affords a physiologically-acceptable cation, for example a salt with methylamine, dimethylamine, trimethylamine, piperidine, morpholine or tris-(2-hydroxyethyl)amine.
  • a further feature of the invention is a pharmaceutical composition
  • a pharmaceutical composition comprising a compound of Formula (I) as defined above, or a pharmaceutically-acceptable salt thereof, together with a pharmaceutically-acceptable diluent or carrier.
  • Formula (I) as defined above or a pharmaceutically-acceptable salt thereof for use as a medicament According to another aspect of the invention there is provided a compound of Formula (I), or a pharmaceutically-acceptable salt thereof as defined above for use as a medicament for treatment of a disease mediated through GLK, in particular type 2 diabetes. Further according to the invention there is provided the use of a compound of
  • the compound is suitably formulated as a pharmaceutical composition for use in this way.
  • GLK mediated diseases especially diabetes
  • a method of treating GLK mediated diseases, especially diabetes by administering an effective amount of a compound of Formula (I) or a pharmaceutically-acceptable salt thereof, including the compounds mentioned in the provisos, to a mammal in need of such treatment.
  • Specific diseases which may be treated by a compound or composition of the invention include: blood glucose lowering in Type 2 Diabetes Mellitus without a serious risk of hypoglycaemia (and potential to treat type 1), dyslipidemia, obesity, insulin resistance, metabolic syndrome X, impaired glucose tolerance.
  • the GLK system can be described as a potential "Diabesity" target (of benefit in both Diabetes and Obesity).
  • a compound of Formula (I) or a pharmaceutically-acceptable salt thereof in the preparation of a medicament for use in the combined treatment or prevention, particularly treatment, of diabetes and obesity.
  • a method for the combined treatment of obesity and diabetes by administering an effective amount of a compound of Formula (I) or a pharmaceutically-acceptable salt thereof, to a mammal in need of such treatment.
  • a compound of Formula (I) or a pharmaceutically-acceptable salt thereof as defined above for use as a medicament for treatment or prevention, particularly treatment of obesity.
  • a method for the treatment of obesity by administering an effective amount of a compound of Formula (I) or a pharmaceutically-acceptable salt thereof, to a mammal in need of such treatment.
  • compositions of the invention may be particularly suitable for use as pharmaceuticals, for example because of favourable physical and/or pharmacokinetic properties and/or toxicity profile.
  • the compositions of the invention may be in a form suitable for oral use (for example as tablets, lozenges, hard or soft capsules, aqueous or oily suspensions, emulsions, dispersible powders or granules, syrups or elixirs), for topical use (for example as creams, ointments, gels, or aqueous or oily solutions or suspensions), for administration by inhalation (for example as a finely divided powder or a liquid aerosol), for administration by insufflation (for example as a finely divided powder) or for parenteral administration (for example as a sterile aqueous or oily solution for intravenous, subcutaneous, intramuscular or intramuscular dosing or as a suppository for rectal dosing). Dosage forms suitable for oral use are preferred.
  • compositions of the invention may be obtained by conventional procedures using conventional pharmaceutical excipients, well known in the art.
  • compositions intended for oral use may contain, for example, one or more colouring, sweetening, flavouring and/or preservative agents.
  • Suitable pharmaceutically acceptable excipients for a tablet formulation include, for example, inert diluents such as lactose, sodium carbonate, calcium phosphate or calcium carbonate, granulating and disintegrating agents such as corn starch or algenic acid; binding agents such as starch; lubricating agents such as magnesium stearate, stearic acid or talc; preservative agents such as ethyl or propyl p_-hydroxybenzoate, and anti-oxidants, such as ascorbic acid.
  • Tablet formulations may be uncoated or coated either to modify their disintegration and the subsequent absorption of the active ingredient within the gastrointestinal tract, or to improve their stability and/or appearance, in either case, using conventional coating agents and procedures well known in the art.
  • Compositions for oral use may be in the form of hard gelatin capsules in which the active ingredient is mixed with an inert solid diluent, for example, calcium carbonate, calcium phosphate or kaolin, or as soft gelatin capsules in which the active ingredient is mixed with water or an oil such as peanut oil, liquid paraffin, or olive oil.
  • an inert solid diluent for example, calcium carbonate, calcium phosphate or kaolin
  • water or an oil such as peanut oil, liquid paraffin, or olive oil.
  • Aqueous suspensions generally contain the active ingredient in finely powdered form together with one or more suspending agents, such as sodium carboxymethylcellulose, methylcellulose, hydroxypropylmethylcellulose, sodium alginate, polyvinyl-pyrrolidone, gum tragacanth and gum acacia; dispersing or wetting agents such as lecithin or condensation products of an alkylene oxide with fatty acids (for example polyoxethylene stearate), or condensation products of ethylene oxide with long chain aliphatic alcohols, for example heptadecaethyleneoxycetanol, or condensation products of ethylene oxide with partial esters derived from fatty acids and a hexitol such as polyoxyethylene sorbitol monooleate, or condensation products of ethylene oxide with long chain aliphatic alcohols, for example heptadecaethyleneoxycetanol, or condensation products of ethylene oxide with partial esters derived from fatty acids and a hexitol such as polyoxyethylene sorbitol
  • the aqueous suspensions may also contain one or more preservatives (such as ethyl or propyl p_-hydroxybenzoate, anti-oxidants (such as ascorbic acid), colouring agents, flavouring agents, and/or sweetening agents (such as sucrose, saccharine or aspartame).
  • preservatives such as ethyl or propyl p_-hydroxybenzoate, anti-oxidants (such as ascorbic acid), colouring agents, flavouring agents, and/or sweetening agents (such as sucrose, saccharine or aspartame).
  • Oily suspensions may be formulated by suspending the active ingredient in a vegetable oil (such as arachis oil, olive oil, sesame oil or coconut oil) or in a mineral oil (such as liquid paraffin).
  • the oily suspensions may also contain a thickening agent such as beeswax, hard paraffin or cetyl alcohol. Sweetening agents such as those set out above, and flavouring agents may be added to provide a palatable oral preparation. These compositions may be preserved by the addition of an anti-oxidant such as ascorbic acid.
  • Dispersible powders and granules suitable for preparation of an aqueous suspension by the addition of water generally contain the active ingredient together with a dispersing or wetting agent, suspending agent and one or more preservatives. Suitable dispersing or wetting agents and suspending agents are exemplified by those already mentioned above. Additional excipients such as sweetening, flavouring and colouring agents, may also be present.
  • the pharmaceutical compositions of the invention may also be in the form of oil- in-water emulsions.
  • the oily phase may be a vegetable oil, such as olive oil or arachis oil, or a mineral oil, such as for example liquid paraffin or a mixture of any of these.
  • Suitable emulsifying agents may be, for example, naturally-occurring gums such as gum acacia or gum tragacanth, naturally-occurring phosphatides such as soya bean, lecithin, an esters or partial esters derived from fatty acids and hexitol anhydrides (for example sorbitan monooleate) and condensation products of the said partial esters with ethylene oxide such as polyoxyethylene sorbitan monooleate.
  • the emulsions may also contain sweetening, flavouring and preservative agents.
  • Syrups and elixirs may be formulated with sweetening agents such as glycerol, propylene glycol, sorbitol, aspartame or sucrose, and may also contain a demulcent, preservative, flavouring and/or colouring agent.
  • the pharmaceutical compositions may also be in the form of a sterile injectable aqueous or oily suspension, which may be formulated according to known procedures using one or more of the appropriate dispersing or wetting agents and suspending agents, which have been mentioned above.
  • a sterile injectable preparation may also be a sterile injectable solution or suspension in a non-toxic parenterally-acceptable diluent or solvent, for example a solution in 1,3-butanediol.
  • Compositions for administration by inhalation may be in the form of a conventional pressurised aerosol arranged to dispense the active ingredient either as an aerosol containing finely divided solid or liquid droplets.
  • Conventional aerosol propellants such as volatile fluorinated hydrocarbons or hydrocarbons may be used and the aerosol device is conveniently arranged to dispense a metered quantity of active ingredient.
  • a formulation intended for oral administration to humans will generally contain, for example, from 0.5 mg to 2 g of active agent compounded with an appropriate and convenient amount of excipients which may vary from about 5 to about 98 percent by weight of the total composition.
  • Dosage unit forms will generally contain about 1 mg to about 500 mg of an active ingredient.
  • Routes of Administration and Dosage Regimes the reader is referred to Chapter 25.3 in Volume 5 of Comprehensive Medicinal Chemistry (Corwin Hansch; Chairman of Editorial Board), Pergamon Press 1990.
  • the size of the dose for therapeutic or prophylactic purposes of a compound of the Formula (I) will naturally vary according to the nature and severity of the conditions, the age and sex of the animal or patient and the route of administration, according to well known principles of medicine.
  • a daily dose in the range for example, 0.5 mg to 75 mg per kg body weight is received, given if required in divided doses.
  • a parenteral route is employed.
  • a dose in the range for example, 0.5 mg to 30 mg per kg body weight will generally be used.
  • a dose in the range for example, 0.5 mg to 25 mg per kg body weight will be used.
  • Oral administration is however preferred.
  • the elevation of GLK activity described herein may be applied as a sole therapy or in combination with one or more other substances and/or treatments for the indication being treated.
  • the invention provides a pharmaceutical combination comprising a compound of Formula I and another pharmacologically active substance particularly wherein the other pharmacologically active substance is a medicament for the treatment of type 2 diabetes or obesity or a related condition.
  • Such conjoint treatment may be achieved by way of the simultaneous, sequential or separate administration of the individual components of the treatment.
  • Simultaneous treatment may be in a single tablet or in separate tablets.
  • chemotherapy may include the following main categories of treatment: 1) Insulin and insulin analogues; 2) Insulin secretagogues including sulphonylureas (for example glibenclamide, glipizide), prandial glucose regulators (for example repaglinide, nateglinide); 3) Agents that improve incretin action (for example dipeptidyl peptidase IV inhibitors e.g.saxagliptin, sitagliptin, vildagliptin or alogliptin and GLP-I agonists);
  • dipeptidyl peptidase IV inhibitors e.g.saxagliptin, sitagliptin, vildagliptin or alogliptin and GLP-I agonists
  • Insulin sensitising agents including PPARgamma agonists (for example pioglitazone and rosiglitazone), and agents with combined PPARalpha and gamma activity;
  • Agents that modulate hepatic glucose balance for example metformin, fructose 1,
  • SGLT inhibitors for example dapagliflozin
  • Agents designed to treat the complications of prolonged hyperglycaemia for example aldose reductase inhibitors
  • Anti-obesity agents for example sibutramine and orlistat
  • Anti- dyslipidaemia agents such as, HMG-CoA reductase inhibitors (eg statins); PP ARa agonists (f ⁇ brates, eg gemfibrozil); bile acid sequestrants (cholestyramine); cholesterol absorption inhibitors (plant stanols, synthetic inhibitors); bile acid absorption inhibitors (IBATi) and nicotinic acid and analogues (niacin and slow release formulations);
  • HMG-CoA reductase inhibitors eg statins
  • PP ARa agonists f ⁇ brates, eg gemfibrozil
  • bile acid sequestrants cholesterol absorption inhibitors
  • plant stanols, synthetic inhibitors bile acid absorption inhibitors
  • IBATi bile acid absorption inhibitors
  • nicotinic acid and analogues nicotinic acid and analogues
  • Antihypertensive agents such as, ⁇ blockers (eg atenolol, inderal); ACE inhibitors (eg lisinopril); Calcium antagonists (eg. nifedipine); Angiotensin receptor antagonists (eg candesartan), ⁇ antagonists and diuretic agents (eg. furosemide, benzthiazide); 12)Haemostasis modulators such as, antithrombotics, activators of fibrinolysis and antiplatelet agents; thrombin antagonists; factor Xa inhibitors; factor Vila inhibitors); antiplatelet agents (eg.
  • ⁇ blockers eg atenolol, inderal
  • ACE inhibitors eg lisinopril
  • Calcium antagonists eg. nifedipine
  • Angiotensin receptor antagonists eg candesartan
  • ⁇ antagonists and diuretic agents eg. furosemide, benzthiazide
  • Anti-inflammatory agents such as non-steroidal anti-inflammatory drugs (eg. aspirin) and steroidal anti-inflammatory agents (eg. cortisone). According to another aspect of the present invention there is provided individual compounds produced as end products in the Examples set out below and salts thereof.
  • a compound of the invention, or a salt thereof may be prepared by any process known to be applicable to the preparation of such compounds or structurally related compounds.
  • Functional groups may be protected and deprotected using conventional methods.
  • protecting groups such as amino and carboxylic acid protecting groups (as well as means of formation and eventual deprotection), see T.W. Greene and P.G.M. Wuts, "Protective Groups in Organic Synthesis", Second Edition, John Wiley & Sons, New York, 1991.
  • R 1 , R 2 , R 3 , R 5 and R 6 are as defined above and X 1 is a leaving group, for example halo, particularly chloro, with a compound of formula (III)
  • R 2 , R 3 and L are as defined above in an inert solvent, for example tetrahydrofuran, in the presence of a base, for example lithium bis(trimethylsilyl)amide or sodium hydride, at a temperature in the range of -25 0 C to 15O 0 C.
  • an inert solvent for example tetrahydrofuran
  • a base for example lithium bis(trimethylsilyl)amide or sodium hydride
  • R 2 , R 3 and L are as defined above and X 2 is a leaving group for example halo particularly chloro, in an inert solvent, for example tetrahydrofuran or dimethylformamide, in the presence of a base, for example potassium carbonate, at a temperature in the range of -25 0 C to 15O 0 C.
  • a base for example potassium carbonate
  • R 2 is as defined above and X 2 is a leaving group, for example halo, particularly bromo, and Y is chloro with a compound of formula (VII)
  • R 3 is as previously defined in the presence of a base, for example di-iso- propylethylamine, in an inert solvent for example dichloromethane at a temperature in the range of -25 0 C to 15O 0 C.
  • a base for example di-iso- propylethylamine
  • an inert solvent for example dichloromethane
  • R 1 , R 5 , R 6 and L are as defined above and R x is a (l-4C)alkyl with a compound of formula (VII) as defined above in an inert solvent, for example tetrahydrofuran, in the presence of a base, for example sodium hydride, at a temperature in the range of -25 0 C to 15O 0 C or in the presence of a Lewis acid, for example trimethyl aluminium in a suitable solvent such as toluene.
  • an inert solvent for example tetrahydrofuran
  • a base for example sodium hydride
  • step a) of Scheme 1 Ring opening of epoxyesters by alcohols as shown in step a) of Scheme 1 is known in the art, see Synthetic Communications, VoI 33 (2003), pp687-692.
  • the reaction generally requires the use of a Lewis acid catalyst, and specifically magnesium perchlorate (Mg(Cl ⁇ 4)2) is known in the above reference, used without any added solvent.
  • Mg(Cl ⁇ 4)2 magnesium perchlorate
  • step a) is carried out in the presence of magnesium trifluoromethanesulfonate, suitably in ethyl acetate, toluene or dichloromethane, most particularly in ethyl acetate.
  • This process is exemplified in Intermediate C7a hereinafter.
  • Suitable examples of RR'NH include
  • R is (l-6C)alkyl. In another aspect, R is methyl, ethyl, isopropyl or cyclobutyl. Although compound of formula (IX) is a methyl ester, other alkyl esters may also be used.
  • the compound of formula (X) may alternatively be reacted with a compound of formula (II) to give a compound of formula (VIII).
  • Compounds of formula (II) may be made according to the following processes a) to b) a) by reaction of a compound of formula (XI) wherein X 3 is a leaving group such as halo (for example chloro), or a precursor to the linker group L such as OH, or SH, or a precursor to the leaving group such as OH, SMe, S(p-tolyl) or NH 2 ; and wherein LG is a leaving group such as chloro, bromo, iodo or trifluoromethanesulfonyl; R 1 , R 5 , R 6 , A, B, X, Y and Z are as previously defined;
  • a reagent such as methyl formate, a mixture of formic acid and sulfuric acid, or trimethylorthoformate when B is C and a reagent such as nitrous acid when B is N.
  • protecting groups may be removed by any convenient method as described in the literature or known to the skilled chemist as appropriate for the removal of the protecting group in question, such methods being chosen so as to effect removal of the protecting group with minimum disturbance of groups elsewhere in the molecule.
  • protecting groups are given below for the sake of convenience, in which "lower” signifies that the group to which it is applied preferably has 1-4 carbon atoms. It will be understood that these examples are not exhaustive. Where specific examples of methods for the removal of protecting groups are given below these are similarly not exhaustive. The use of protecting groups and methods of deprotection not specifically mentioned is of course within the scope of the invention.
  • a carboxy protecting group may be the residue of an ester- forming aliphatic or araliphatic alcohol or of an ester- forming silanol (the said alcohol or silanol preferably containing 1-20 carbon atoms).
  • carboxy protecting groups include straight or branched chain (l-12C)alkyl groups (e.g. isopropyl, t-butyl); lower alkoxy lower alkyl groups (e.g. methoxymethyl, ethoxymethyl, isobutoxymethyl; lower aliphatic acyloxy lower alkyl groups, (e.g. acetoxymethyl, propionyloxymethyl, butyryloxymethyl, pivaloyloxymethyl); lower alkoxycarbonyloxy lower alkyl groups (e.g.
  • aryl lower alkyl groups e.g. p_-methoxybenzyl, o-nitrobenzyl, p_-nitrobenzyl, benzhydryl and phthalidyl
  • tri(lower alkyl)silyl groups e.g. trimethylsilyl and t-butyldimethylsilyl
  • tri(lower alkyl)silyl lower alkyl groups e.g. trimethylsilylethyl
  • (2-6C)alkenyl groups e.g. allyl and vinylethyl.
  • hydroxy protecting groups include methyl, t-butyl, lower alkenyl groups (e.g. allyl); lower alkanoyl groups (e.g. acetyl); lower alkoxycarbonyl groups (e.g. t-butoxycarbonyl); lower alkenyloxycarbonyl groups (e.g. allyloxycarbonyl); aryl lower alkoxycarbonyl groups (e.g. benzoyloxycarbonyl, p_-methoxybenzyloxycarbonyl, o-nitrobenzyloxycarbonyl, p_-nitrobenzyloxycarbonyl); tri lower alkyl/arylsilyl groups (e.g.
  • amino protecting groups include formyl, aralkyl groups (e.g. benzyl and substituted benzyl, e.g. p_-methoxybenzyl, nitrobenzyl and 2,4-dimethoxybenzyl, and triphenylmethyl); di-p_-anisylmethyl and furylmethyl groups; lower alkoxycarbonyl (e.g.
  • t-butoxycarbonyl lower alkenyloxycarbonyl (e.g. allyloxycarbonyl); aryl lower alkoxycarbonyl groups (e.g. benzyloxycarbonyl, p_-methoxybenzyloxycarbonyl, o-nitrobenzyloxycarbonyl, p_-nitrobenzyloxycarbonyl; trialkylsilyl (e.g. trimethylsilyl and t-butyldimethylsilyl); alkylidene (e.g. methylidene); benzylidene and substituted benzylidene groups.
  • aryl lower alkoxycarbonyl groups e.g. benzyloxycarbonyl, p_-methoxybenzyloxycarbonyl, o-nitrobenzyloxycarbonyl, p_-nitrobenzyloxycarbonyl
  • trialkylsilyl e.g. trimethylsilyl and t-butyldimethylsily
  • Methods appropriate for removal of hydroxy and amino protecting groups include, for example, nucleophilic displacement, acid-, base, metal- or enzymically-catalysed hydrolysis, catalytic hydrogenolysis/hydrogenation or photolytically for groups such as o-nitrobenzyloxycarbonyl, or with fluoride ions for silyl groups.
  • methylether protecting groups for hydroxy groups may be removed by trimethylsilyliodide.
  • a tert-butyl ether protecting group for a hydroxy group may be removed by hydrolysis, for example by use of hydrochloric acid in methanol.
  • protecting groups for amide groups include aralkoxymethyl (e.g. benzyloxymethyl and substituted benzyloxymethyl); alkoxymethyl (e.g. methoxymethyl and trimethylsilylethoxymethyl); tri alkyl/arylsilyl (e.g. trimethylsilyl, t-butyldimethylsily, t-butyldiphenylsilyl); tri alkyl/arylsilyloxymethyl (e.g. t-butyldimethylsilyloxymethyl, t-butyldiphenylsilyloxymethyl); 4-alkoxyphenyl (e.g. 4-methoxyphenyl); 2,4- di(alkoxy)phenyl (e.g.
  • 2,4-dimethoxyphenyl 4-alkoxybenzyl (e.g. 4-methoxybenzyl); 2,4-di(alkoxy)benzyl (e.g. 2,4-di(methoxy)benzyl); and alk-1-enyl (e.g. allyl, but-1-enyl and substituted vinyl e.g. 2-phenylvinyl).
  • 4-alkoxybenzyl e.g. 4-methoxybenzyl
  • 2,4-di(alkoxy)benzyl e.g. 2,4-di(methoxy)benzyl
  • alk-1-enyl e.g. allyl, but-1-enyl and substituted vinyl e.g. 2-phenylvinyl
  • Aralkoxymethyl, groups may be introduced onto the amide group by reacting the latter group with the appropriate aralkoxymethyl chloride, and removed by catalytic hydrogenation.
  • Alkoxymethyl, tri alkyl/arylsilyl and tri alkyl/silyloxymethyl groups may be introduced by reacting the amide with the appropriate chloride and removing with acid; or in the case of the silyl containing groups, fluoride ions.
  • the alkoxyphenyl and alkoxybenzyl groups are conveniently introduced by arylation or alkylation with an appropriate halide and removed by oxidation with eerie ammonium nitrate.
  • alk-1- enyl groups may be introduced by reacting the amide with the appropriate aldehyde and removed with acid.
  • Enantiomeric excesses were determined by HPLC using a chiral stationary phase such as Chiralcel OJ or Chiralpak AD-H and / or by NMR using an appropriate chiral shift reagent such as (IS)-[I, r-binaphthalene]-2,2'-diol (CAS 18531-99- 2) or (IR)-[I, r-binaphthalene]-2,2'-diol (CAS 18531-94-7).
  • a chiral stationary phase such as Chiralcel OJ or Chiralpak AD-H and / or by NMR using an appropriate chiral shift reagent such as (IS)-[I, r-binaphthalene]-2,2'-diol (CAS 18531-99- 2) or (IR)-[I, r-binaphthalene]-2,2'-diol (CAS 18531-94-7).
  • Example 13 4-methoxy-2- ⁇ [l-(3-methoxyphenyl)-lH-pyrazolo[3,4- ⁇ /]pyrimidin-4- yl]oxy ⁇ -7V-(5-methylpyridin-2-yl)butanamide
  • ⁇ i]pyrimidin-4-yl]oxy ⁇ - ⁇ /-(5-methylpyridin-2-yl)butanamide 100 mg were separated by preparative ⁇ PLC: Column Chiralpak AS (250x20 mm, 5 ⁇ m); Mobile phase heptane/IPA:60/40; Flow 13 ml/min; UV 275 nm; Temperature 4O 0 C.
  • Example 28 4-Methoxy-7V-(5-methylpyridin-2-yl)-2-( ⁇ l-[2-(trifluoromethyl)phenyl]- lH-pyrazolo [3,4- ⁇ /] pyrimidin-4-yl ⁇ oxy)butanamide
  • Example 48 3-Acetamido-2- ⁇ [l-(2-chlorophenyl)-l ⁇ -pyrazolo[3,4- ⁇ /]pyrimidin-4- yl]oxy ⁇ -n-(4-methyl-l,3-thiazol-2-yl)propanamide
  • Example 54 2- ⁇ [l-(2-chlorophenyl)-lH-pyrazolo[3,4- ⁇ /]pyrimidin-4-yl]thio ⁇ -3-methyl- 7V-(4-methyl- 1 ,3-thiazol-2-yl)pentanamide
  • reaction mixture was kept at ambient temperature for 25 minutes before it was added to a solution of l-(2- chlorophenyl)-lH-pyrazolo[3,4-d]pyrimidine-4-thiol (130 mg, 0.495 mmol) and anhydrous potassium carbonate (102.6 mg, 0.742 mmol) in DMF (3 mL).
  • the reaction mixture was kept at ambient temperature for 3 hrs. Water and EtOAc were added and the two phases were separated. The aqueous phase was extracted with EtOAc. The organic extracts were combined and washed three times with water, dried over MgSO 4 and concentrated in vacuo.
  • Ci 9 Hi 8 35 ClN 6 O 2 S 2 461.0621. Found: 461.0631.
  • Example 84 (2S)-2-( 1 -(2-chlorophenyl)- 1 H-pyrazolo [3 ,4-d]pyrimidin-4-yloxy)-3 -methyl- JV-(5-methylpyridin-2-yl)butanamide
  • Example 85 (2R)-2-(l -(2-chlorophenyl)- 1 H-pyrazolo [3, 4-d]pyrimidin-4-yloxy)-3-methyl- JV-(5-methylpyridin-2-yl)butanamide
  • Example 86 (2S)-2-(l-(3-chloropyridin-2-yl)-lH-pyrazolo[3,4-d]pyrimidin-4-yloxy)-3- methyl- ⁇ /-(5-methylpyridin-2-yl)butanamide
  • Example 87 (2S)-2-( 1 -(2-chlorophenyl)- 1 H-pyrazolo [3 ,4-d]pyrimidin-4-yloxy)-3 - methoxy- ⁇ /-(5-methylpyridin-2-yl)propanamide
  • Example 88 (2R)-2-(l-(2-chlorophenyl)-lH-pyrazolo[3,4-d]pyrimidin-4-yloxy)-3- methoxy- ⁇ /-(5-methylpyridin-2-yl)propanamide
  • Example 89 (2S)-2-(l-(3-chloropyridin-2-yl)-lH-pyrazolo[3,4-d]pyrimidin-4-yloxy)-3- methoxy- ⁇ /-(5-methylpyridin-2-yl)propanamide
  • Example 93 (2S)-2-(l-(3-chloropyridin-2-yl)-lH-pyrazolo[3,4-d]pyrimidin-4-yloxy)-3- isopropoxy-N-(3 -methyl- 1 ,2,4-thiadiazol-5-yl)propanamide
  • Example 94 (2S)-2-(l-(3-chloropyridin-2-yl)-lH-pyrazolo[3,4-d]pyrimidin-4-yloxy)-3- methyl- ⁇ /-(5-methylpyrazin-2-yl)butanamide
  • the resulting solution was stirred at room temperature for 24 hours.
  • the reaction mixture was diluted with DCM (25 mL) and washed with saturated brine (20 mL).
  • the aqueous layer was re-extracted with DCM (30 mL).
  • the combined organics were evaporated to afford crude product.
  • the crude product was purified by flash silica chromatography, elution gradient 20 to 50% EtOAc in isohexane.
  • Example 109 2-[l-(2-chlorophenyl)pyrazolo[4,5-e]pyrimidin-4-yl]oxy-3-isopropoxy-N-
  • Example 112 2-[l-(2-chlorophenyl)pyrazolo[4,5-e]pyrimidin-4-yl]oxy-N-(5-fluoro-2- pyridyl)-3-isopropoxy-propanamide
  • Example 115 2-[l-(2-chlorophenyl)pyrazolo[4,5-e]pyrimidin-4-yl]oxy-N-(5-chloro-2- pyridyl)-3-isopropoxy-propanamide
  • Example 116 2-[l-(2-chlorophenyl)pyrazolo[4,5-e]pyrimidin-4-yl]oxy-3-isopropoxy-N-
  • Example 120 2-[l-(2-chlorophenyl)pyrazolo[4,5-e]pyrimidin-4-yl]oxy-3-isopropoxy-N- pyrimidin-4-yl-propanamide
  • Example 111a (2S)-2-[l-(2-chlorophenyl)pyrazolo[4,5-e]pyrimidin-4-yl]oxy-3- isopropoxy-N-(5-methylthiazol-2-yl)propanamide
  • Example 112a (2S)-2-[l-(2-chlorophenyl)pyrazolo[4,5-e]pyrimidin-4-yl]oxy-N-(5-fluoro-
  • Example 125 The following Examples were prepared using a method analogous to that described for Example 125 using the appropriate ester and arylamine.
  • Example 127a (2S)-N-(5-cyanopyridin-2-yl)-3-isopropoxy-2-(l-(3-methylpyridin-2-yl)- 1 H-pyrazolo [3 ,4-d]pyrimidin-4-yloxy)propanamide
  • Example 127c (2S)-2-[l-(3-chloro-2-pyridyl)pyrazolo[4,5-e]pyrimidin-4-yl]oxy-N-(5- cyano-2-pyridyl)-3-ethoxy-propanamide
  • Example 127d (2S)-2-[l-(3-chloro-2-pyridyl)pyrazolo[4,5-e]pyrimidin-4-yl]oxy-3- ethoxy-N-(5-fluoro-2-pyridyl)propanamide
  • Example 127h (2S)-2-[l-(3-chloro-2-pyridyl)pyrazolo[4,5-e]pyrimidin-4-yl]oxy-N-(4- cyanothiazol-2-yl)-3-isopropoxy-propanamide
  • Example 127i (2S)-N-(5-chloro-2-pyridyl)-2-[l-(3-chloro-2-pyridyl)pyrazolo[4,5- e]pyrimidin-4-yl]oxy-3-isopropoxy-propanamide
  • Example 128 (2S)-N-(5-Chloropyridin-2-yl)-3-ethoxy-2-[l-(3-methylpyridin-4- yl)pyrazolo [4,5-e] pyrimidin-4-yl] oxypr opanamide 60% Sodium hydride in mineral oil (48.8mg, 1.22 mmol) was added in one portion to (S)- N-(5-chloropyridin-2-yl)-3-ethoxy-2-hydroxypropanamide (Intermediate H3) (199 mg, 0.81 mmol) in anhydrous THF (5 mL) cooled to 0 0 C under nitrogen.
  • Example 128 The following Examples were prepared using a method analogous to that described for Example 128 using the alcohol and chloro derivative.
  • Example 128a (2S)-N-(5-chloropyridin-2-yl)-3-ethoxy-2-(l-(3-methylpyridin-2-yl)-lH- pyrazolo [3 ,4-d]pyrimidin-4-yloxy)propanamide
  • Phosphorus oxychloride (1.864 ml, 20.00 mmol) was added to l-(2- (methylsulfonyl)phenyl)-lH-pyrazolo[3,4-d]pyrimidin-4-ol (Intermediate Nl) (0.290 g, 1 mmol), at ambient temperature. The resulting mixture was stirred at 100 0 C for 4 hours. The solution was allowed to cool to ambient temperature. The reaction mixture was evaporated. The residue was dissolved in DCM (30 mL). MP-Carbonate was added and the mixture stirred for 30 minutes then evaporated. The residue was dissolved in THF (5 mL).
  • reaction mixture was diluted with DCM (20 mL) washed with 2M NaOH (20 mL), dried (MgSO 4 ) and evaporated. The residue was purified by flash silica chromatography, eluting with 10 to 100% ethyl acetate in isohexane to afford the product (80 mg).
  • Trimethylaluminium (0.347 mL, 0.69 mmol) was added to 5-methylpyridin-2-amine (71.7 mg, 0.66 mmol) in toluene (8 mL) cooled to O 0 C under nitrogen. The resulting solution was stirred at O 0 C for 20 minutes.
  • (3S)-3-(l-(3-chloropyridin-2-yl)-lH-pyrazolo[3,4- d]pyrimidin-4-yloxy)dihydrofuran-2(3H)-one (Intermediate Tl) (200 mg, 0.60 mmol) in toluene (2 rnL) and the reaction was allowed to warm to room temperature and stirred for 1 hour.
  • the reaction was then heated at 5O 0 C for 2 hours.
  • the reaction mixture was allowed to cool and was neutralised with citric acid (IM, aq.) and then diluted with water (50 mL) and ethyl acetate (50 mL).
  • the organic layer was separated and the aqueous layer re- extracted with ethyl acetate (50 mL).
  • the combined organics were dried (MgSO 4 ), filtered and evaporated.
  • the crude product was purified by flash silica chromatography, eluting with 0 to 10% MeOH in DCM to afford the product (185 mg, 69.8 %).
  • the reaction mixture was neutralised with IM citric acid and the majority of the THF removed in vacuo.
  • the reaction mixture was diluted with water (20 mL) and ethyl acetate (50 mL).
  • the organic layer was separated and the aqueous layer re-extracted with ethyl acetate (2 x 50 mL).
  • the combined organics were washed with saturated brine (25 mL), dried (MgSC ⁇ ) and evaporated.
  • the crude product was purified by flash silica chromatography, eluting with 0 to 5% MeOH in DCM to afford the product (78 mg, 41.6 %).
  • the reaction mixture was diluted with water (20 mL) and ethyl acetate (50 mL). The organic layer was separated and the aqueous layer re-extracted with ethyl acetate (2 x 20 mL). The combined organics were washed with saturated brine (10 mL), dried (MgSO ⁇ and evaporated. The crude product was purified by flash silica chromatography, eluting with 0 to 5% MeOH in DCM to afford the product (24.0 mg, 11.8%).

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Abstract

L'invention porte sur un composé représenté par la formule (I) utile pour le traitement ou la prévention d'une maladie ou d'un état médical à médiation par la glucokinase (GLK ou GK) qui baisse le seuil de sécrétion d'insuline.
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CN108033966A (zh) * 2018-01-05 2018-05-15 天津药明康德新药开发有限公司 7-叔丁基3-乙基8-甲基5,6二氢三唑并吡嗪3,7(8h)二甲酸基酯的合成方法
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WO2010015849A2 (fr) 2010-02-11
BRPI0917589A2 (pt) 2015-11-17
AU2009278929A1 (en) 2010-02-11
SV2011003829A (es) 2011-07-01
AU2009278929B2 (en) 2012-07-05
ZA201101663B (en) 2011-11-30
CA2732165A1 (fr) 2010-02-11
US8143263B2 (en) 2012-03-27
KR20110052676A (ko) 2011-05-18
DOP2011000047A (es) 2011-02-28
MX2011001333A (es) 2011-03-15
US20100093757A1 (en) 2010-04-15
WO2010015849A3 (fr) 2010-04-01
CN102171213A (zh) 2011-08-31
CO6351730A2 (es) 2011-12-20
CR20110065A (es) 2011-05-10
UY32032A (es) 2010-03-26
PE20110568A1 (es) 2011-09-07
AU2009278929A8 (en) 2011-03-10
JP2011529955A (ja) 2011-12-15
EA201100097A1 (ru) 2011-10-31
TW201011026A (en) 2010-03-16
CL2011000249A1 (es) 2011-07-15
AR072900A1 (es) 2010-09-29
IL210778A0 (en) 2011-03-31
ECSP11010809A (es) 2011-03-31

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